1. Field of the Invention
This invention relates to novel antibacterial agents which are of value as animal feed supplements, and to novel intermediates for their production. More specifically, the antibacterial compounds of the invention are certain 6-acylamino-2,2-dimethyl-3-phosphonopenams, the corresponding 6-acylamino-2,2-dimethyl-3-(O-methylphosphono)penams and 6-acylamino-2,2-dimethyl-3-(O,O-dimethylphosphono)penams and pharmaceutically acceptable salts thereof, as well as processes and novel intermediates for their production.
2. Description of the Prior Art
In spite of the large number of penam derivatives which have been proposed for use as antibacterial agents, there still exists a need for new agents.
The vast majority of penam compounds disclosed in the prior art have carboxylic acid group (or a salt thereof) attached to the 3-position. However, penam compounds with other carboxylic acid derivatives at the C-3 locus are also known. Penam-3-carboxylic acid esters have been disclosed, for example, by Kirchner et al., Journal of Organic Chemistry, 14, 388 (1949); Carpenter, Journal of the American Chemical Society, 70, 2964 (1948); Johnson, Journal of the American Chemical Society, 75, 3636 (1953); Barnden et al., Journal of the Chemical Society (London), 3733 (1953) and Jansen and Russell, Journal of the Chemical Society (London), 2127 (1965); and penam-3-carboxamides have been reported, for example, by Holysz and Stavely, Journal of the American Chemical Society, 72, 4760 (1950) and Huang et al., Antimicrobial Agents and Chemotherapy, 493 (1963). Peron et al. (Journal of Medicinal Chemistry, 7, 483 [1964])prepared several6-(substituted amino)-2,2-dimethyl-penam-3 -carboxylic acid azides, which were subsequently converted into the corresponding 3-isocyanates and 3-benzylcarbamates. Peron et al. (loc. cit.) also reported certain 3-(hydroxymethyl)penam derivatives. Dehydration of the simple amide of benzylpenicillin yields the corresponding nitrile (Khokhlov et al., Doklady Akad, Sci. Nauk S.S.S.R., 135, 875 [1960]).
3-(5-Tetrazolyl)penams were disclosed in Belgian Pat. No. 821,163.
Phosphorylated penicillanic and cephalosporanic acids, prepared by reaction of the corresponding 3- or 4-carboxylic acids, respectively, with a phosphorus halide are reported in U.S. Pat. No. 3,875,152. .alpha.-(phosphono)- and .alpha.-(phosphonoalkyl)-cephalosporins in which the phosphorus containing group is incorporated into the 7-acyl side chain are the subject of U.S. Pat. No. 3,870,713.
West German Specification No. 2,364,735 disclosed cephalosporins in which phosphono, sulfo or sulfonamido groups are attached at the 4-position of the cephem nucleus by total synthesis.
Regarding the prior art pertinent to the disclosed intermediates for preparation of the compounds of the invention, Heusler, Helvetica Chimica Acta, 55, 388 (1972), has reported the synthesis of .alpha.-phenoxyacetamido-5,5-dimethyl-3-thiazoline-2-acetic acid piperidide by reacting 6-phenoxyacetamido-2,2-dimethyl-3-hydroxypenam with piperidine benzoate in acetontrile as solvent. Heusler (loc. cit.), and Barton et al., J. Chem. Soc., Perkin I, 599 (1973), have reported on methods of synthesis of 3-hydroxy-penam derivatives containing 6-phenylacetamido and 6-phenoxyacetamido moieties. Barton (loc. cit. and references therein) has also reported the corresponding S-oxides. However, 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam is not previously disclosed and neither is the lead tetraacetate method for preparation of 3-acetoxypenams.
For the sake of convenience, the compounds described herein are identified as derivatives of penam. The term "penam" has been defined in the J. Am. Chem. Soc., 75, 3293 (1953), as referring to the structure: ##STR1## Using this terminology, the well-known antibiotic penicillin G is designated as 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylic acid. The hydrogen methyl phosphonate analog of penicillin G, formula (Ib) below, wherein R.sup.1 is phenyl and Q is hydrogen, is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-(O-methylphosphono)penam. The corresponding dimethyl phosphonate is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-(O,O-dimethylphosphono)penam and the corresponding dibasic phosphonic acid is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-phosphonopenam.